Argininosuccinate Lyase (AL) Deficiency

Argininosuccinate lyase (AL) is also called argininosuccinase. The argininosuccinate lyase gene (symbol: ASL) is located on
chromosome 7q11.21 and is composed of 17 exons that generate four alternatively spliced mRNAs. These four mRNAs give rise to three different isoforms of the AL enzyme. AL isoform 1 is 464 amino acids, isoform 2 is 444 amino acids, and isoform 3 is 438 amino acids. The functional AL enzyme exists as a homotetramer.
The human AL protein is highly similar (60%) to avian and reptilian crystalin
proteins of the lens. Examination of mutations in the AL gene that give rise to
arginiosuccinate lyase deficiency (ALD) from 28 patients has identified at least
12 allelic mutations. Mutations include missense, nonsense and exon deletions.
The inheritance of ALD is autosomal recessive and occurs with a frequency of approximately 1 case per 70,000 live births.

ALD is, like the other neonatal onset
forms of UCDs, most severe when presenting in newborn infants. As with each of
the four neonatal onset UCDs, ALD is characterized by the accumulation of
ammonia and glutamine with clinical manifestations appearing in full-term
infants with no prior obstetric risk factors. The classic symptoms appear
between 24hrs and 48hrs after birth (but not prior to 24hrs) and include
convulsions, hyperventilation, ataxia, hypothermia, lethargy, vomiting and poor
feeding. If left untreated the hyperammonemia with result in coma and death. The
severe effects of hyperammonemia are described in the Nitrogen Metabolism page.
Even though sepsis is a rare event in a normal term infant with no prior
obstetric complications, this disorder is misdiagnosed in almost half of
neonatal UCD cases. Initial laboratory findings will include respiratory
alkalosis which is the earliest objective indication of encephalopathy. The
encephalopathy will progress to the point where mechanical ventilation is
required. Another routine laboratory finding is reduced serum (blood) urea
nitrogen (BUN) which may be as low as 1mg/dl (normal for newborns is 3–12mg/dl).
If plasma ammonia levels are not measured the infants' death will be attributed
to sepsis, intracranial hemorrhage, or some other disorder that would normally
be associated with a pre-term delivery.

ALD patients are treated in much the same ways as for other neonatal UCDs in
that protein intake must me highly regulated and the hyperammonemia must be
controlled. Hemodialysis is the only effective means to rapidly lower serum
ammonia levels in these patients. Acute episodes of hyperammonemia can be treated with intravenous
administration of Ammunol® and with oral Buphenyl® for chronic
adjunctive therapy of hyperammonemia.
Treatment of ALD patients with large amounts oral arginine aids in waste
nitrogen removal. The oral arginine is converted to urea and ornithine via the
arginase reaction of the urea cycle. The ornithine (along with carbamoyl
phosphate) is then converted to citrulline through the action of ornithine
transcarbamoylase (OTC). Citrulline is then converted to argininosuccinate via
the argininosuccinate synthetase reaction which also requires aspartate. The net
effect is that nitrogen in carbamoyl phosphate and arginine is eliminated as
argininosuccinate.